The present invention provides a stabilized growth hormone, a method for its preparation and a process for effecting growth promotion in an animal by administering an effective amount of stabilized growth hormone. The stabilizers decrease the formation of insolubles and preserve the soluble bioactivity of the growth hormone in aqueous environments. One major problem in the administration of growth hormones is the denaturation of the native globular structure causing aggregation of the growth hormone into precipitated forms which decreases the amount of active growth hormone available. The formation of these insolubles can also block tubing, membranes and various pumps of the implanted delivery devices. System failure almost always results due to the formation of these insolubles. In addition to the formation of insolubles, another problem in the administration of growth hormones is retaining the soluble bioactivity of the hormone. Therefore, to properly serve as a stabilizer for growth formulations, the stabilizer must decrease the formation of insolubles and maintain the bioactivity of the soluble growth hormone.
A variety of stabilizers have been disclosed in the art which avoid the breakdown of the structures of proteins. For example, glycerol has been used to stabilize the activity of various proteins. Gekko, et al., Biochemistry (1981), 20, pp. 4666-76. Examples of proteins which are described in this article include chymotrypsinogen A (from bovine pancreas), ribonuclease A (from bovine pancreas), .beta.-lactoglobin (from milk), bovine serum albumin, insulin (bovine pancreatic), egg-white lysozyme and .alpha.-chymotrypsin.
U.S. Pat. No. 4,179,337 discloses a process for coupling a polypeptide such as enzymes and insulin to polyethylene glycol or polypropylene glycol having a molecular weight of 500 to 20,000 daltons. The polyethylene glycol or polypropylene glycol is described as protecting the polypeptide from loss of activity and the composition can be injected without any immunogenic response.
U.S. Pat. No. 4,439,181 discloses a method for preventing the precipitation of proteins within drug delivery systems that depend on the fluidity of the infusate for proper function. The method comprises mixing a polyol with the protein solution prior to introduction of the solution into the drug delivery system. Examples of the polyols which are described include glycerol and biocompatible C-4 to C-18 polyols. Exemplary of the polyols are erythritol, arabinose, xylose, ribose, adonitol, arabitol, rhamose, inositol, fructose, galactose, glucose, mannose, sorbose, maltose, sucrose, melezitose, and raffinose. The solid polyols are dissolved in a standard aqueous insulin solution or are first prepared as an aqueous solution and admixed with the insulin to provide the final concentration of polyol in the solution of about 10 to 90 percent weight per volume, with the balance being the protein. Other proteins which are described as being subject to the same precipitation problems include growth hormone, glucagon and the like.
While the prior art has taught a number of various stabilizers for specific proteins, unfortunately, the fact a particular stabilizer is effective with a particular protein does not necessarily mean that the particular stabilizer is appropriate for the stabilization of a growth promoting hormone. Therefore, there exists a need for a method of stabilization of a growth promoting hormone which decreases the formation of insolubles and preserves the soluble bioactivity of the hormone.